Table of Contents
- Introduction to Gluconeogenesis
- Gluconeogenesis Location
- Steps of Gluconeogenesis
- Precursors
- Gluconeogenesis Pathway
- Gluconeogenesis Regulation
- Importance of Gluconeogenesis
- Associated Disease
- Conclusion
- References
Introduction to Gluconeogenesis
- During fasting or restricted carbohydrate intake, gluconeogenesis is crucial for maintaining normal blood glucose levels.
- This metabolic process generates glucose from non-carbohydrate sources such as lactate, pyruvate, glycerol, and specific amino acids.
- The liver and kidneys serve as the primary sites for gluconeogenesis.
- It is regulated by various hormonal signals.
Gluconeogenesis Location
- The majority of gluconeogenesis takes place in the liver, where glucose is produced and released into the bloodstream.
- The liver has a high capacity for gluconeogenesis due to the presence of essential enzymes involved in the pathway.
- Although to a lesser extent than the liver, the kidneys also contribute to gluconeogenesis.
- The demand for gluconeogenesis rises during extended fasting or prolonged physical activity.
- The liver and kidneys play a vital role in meeting the body's glucose requirements under these conditions.
Steps of Gluconeogenesis
1 – Substrates
- Precursors for gluconeogenesis include lactate, pyruvate, glycerol, and certain amino acids.
- Glycerol is converted into dihydroxyacetone phosphate (DHAP), an intermediate in glycolysis.
- Lactate is converted back into pyruvate.
2 – Conversion of Pyruvate to Phosphoenolpyruvate (PEP)
- Pyruvate carboxylase converts pyruvate into oxaloacetate.
- This process requires ATP and biotin as cofactors.
- Phosphoenolpyruvate carboxykinase (PEPCK), found in the mitochondria and cytoplasm, converts oxaloacetate into PEP.
3 – PEP to Fructose-1,6-bisphosphate
- Multiple enzymatic steps convert PEP to fructose-1,6-bisphosphate, bypassing the irreversible glycolysis reactions.
- PEP is first converted into oxaloacetate, which is then transformed into malate and transported out of the mitochondria.
- Malate is converted back into oxaloacetate in the cytoplasm and phosphorylated to form PEP.
4 – Fructose-1,6-bisphosphate to Glucose
- The later steps of gluconeogenesis reverse glycolysis reactions.
- Fructose-1,6-bisphosphatase removes a phosphate group from fructose-1,6-bisphosphate, producing fructose-6-phosphate.
- Glucose-6-phosphatase hydrolyzes glucose-6-phosphate, allowing glucose to be released into circulation.
Regulation of Gluconeogenesis:
- Hormonal signals and metabolic conditions regulate gluconeogenesis.
- Insulin inhibits gluconeogenesis.
- Glucagon, cortisol, and growth hormone promote gluconeogenesis to maintain blood glucose levels.
Precursors
- Various sources contribute different precursors for gluconeogenesis.
- Lactate, produced through anaerobic metabolism, can be converted back into pyruvate and used as a substrate for gluconeogenesis.
- Pyruvate can also be formed through amino acid transamination or by the release of glycerol from triglyceride breakdown.
- Alanine and glutamine are two amino acids that can directly participate in the gluconeogenic pathway.
Gluconeogenesis Pathway
- Gluconeogenesis consists of a series of enzymatic reactions that reverse several steps of glycolysis.
- Pyruvate is first carboxylated by pyruvate carboxylase to form oxaloacetate.
- Phosphoenolpyruvate carboxykinase (PEPCK) then converts oxaloacetate into phosphoenolpyruvate (PEP).
- Additional enzymes facilitate the conversion of PEP to fructose-1,6-bisphosphate, bypassing the irreversible steps of glycolysis.
- Fructose-1,6-bisphosphatase converts fructose-1,6-bisphosphate, and glucose-6-phosphatase hydrolyzes glucose-6-phosphate, allowing glucose to be released into circulation.
Gluconeogenesis Regulation
- Gluconeogenesis is tightly regulated to ensure glucose synthesis occurs only when needed.
- Hormones such as glucagon, cortisol, and growth hormone promote gluconeogenesis.
- Glucagon is released when blood sugar levels are low, stimulating the production of key gluconeogenic enzymes.
- Growth hormone and cortisol enhance gluconeogenesis, especially during stress or fasting.
- Insulin inhibits gluconeogenesis by downregulating gluconeogenic enzymes and promoting glucose uptake by tissues.
- Hormonal regulation helps maintain glucose homeostasis.
Insulin Resistance
- Insulin resistance disrupts gluconeogenesis regulation by reducing cellular responsiveness to insulin.
- In insulin-resistant states, the liver continues to produce excess glucose due to reduced sensitivity to insulin’s inhibitory effects.
- This contributes to high blood glucose levels, as seen in type 2 diabetes.
- Insulin resistance also suppresses glycolysis, further worsening hyperglycemia.
Importance of Gluconeogenesis
- Gluconeogenesis plays a vital role in maintaining blood sugar levels during periods of fasting or carbohydrate deprivation.
- It provides glucose to essential tissues and cells, including red blood cells, neurons, skeletal muscles, kidney medulla, testes, and embryonic tissues.
- The process helps clear metabolites like lactate, produced by muscles and RBCs, and glycerol, released from adipose tissue, from the circulation.
Associated Disease
- Deficiency in gluconeogenic enzymes can result in hypoglycemia.
- Impaired gluconeogenesis can be life-threatening if the body is unable to produce glucose during fasting or stress conditions.
Conclusion
Gluconeogenesis is a vital metabolic process that maintains blood glucose levels during glucose shortages.
It synthesizes glucose from non-carbohydrate precursors like lactate, pyruvate, glycerol, and certain amino acids.
The liver and kidneys are the primary sites of gluconeogenesis.
Hormonal regulation plays a key role: insulin inhibits the process, while glucagon, cortisol, and growth hormone stimulate it.
Proper regulation ensures glucose is produced only when necessary, preventing hypoglycemia or excessive glucose production.
References
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Lehninger, A. L., Nelson, D. L., & Cox, M. M. (2000). Lehninger principles of biochemistry. New York: Worth Publishers.
John W. Pelley, Edward F. Goljan (2011). Biochemistry. Third edition. Philadelphia: USA.
Madigan, M. T., Martinko, J. M., Bender, K. S., Buckley, D. H., & Stahl, D. A. (2015). Brock biology of microorganisms (Fourteenth edition.). Boston: Pearson.
Rodwell, V. W., Botham, K. M., Kennelly, P. J., Weil, P. A., & Bender, D. A. (2015). Harper’s illustrated biochemistry (30th ed.). New York, N.Y.: McGraw-Hill Education LLC.
Physiology, Gluconeogenesis – https://www.ncbi.nlm.nih.gov/books/NBK541119/
Gluconeogenesis – https://byjus.com/neet/gluconeogenesis-definition/
Gluconeogenesis – https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Supplemental_Modules_(Biological_Chemistry)/Metabolism/Anabolism/Gluconeogenesis
Gluconeogenesis – https://www.britannica.com/science/gluconeogenesis
